COB231 targets amyloid plaques in post‐mortem human brain tissue and in an Alzheimer mouse model

• Published in: Journal of neurochemistry Vol. 132; no. 5; pp. 609 - 618
• Main Authors: Garin, Dominique, Virgone‐Carlotta, Angélique, Gözel, Bülent, Oukhatar, Fatima, Perret, Pascale, Marti‐Battle, Danièle, Touret, Monique, Millet, Philippe, Dubois‐Dauphin, Michel, Meyronet, David, Streichenberger, Nathalie, Laferla, Frank M., Demeunynck, Martine, Chierici, Sabine, Sallanon, Marcelle Moulin, Ghezzi, Catherine
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2015; Wiley
• Subjects: 3xTgAD mice; Alzheimer; Alzheimer Disease; Alzheimer Disease - pathology; Aminacrine; Aminacrine - analogs & derivatives; Aminacrine - chemical synthesis; Aminacrine - chemistry; amyloid plaques; Animals; Autopsy; Bioengineering; Brain; Brain - pathology; Disease Models, Animal; Female; fluorescence; Fluorescent Dyes; Fluorescent Dyes - chemical synthesis; Fluorescent Dyes - chemistry; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Immunohistochemistry - methods; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence; Nuclear medicine; Plaque, Amyloid; Plaque, Amyloid - diagnosis; Proflavine; Proflavine - analogs & derivatives; Sensitivity and Specificity; Staining and Labeling; Staining and Labeling - methods
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12951

Previous works have shown the interest of naturally fluorescent proflavine derivatives to label Abeta deposits in vitro. This study aimed to further characterize the properties of the proflavine 3‐acetylamino‐6‐[3‐(propargylamino)propanoyl]aminoacridine (COB231) derivative as a probe. This compound was therefore evaluated on human post‐mortem and mice brain slices and in vivo in 18‐month‐old triple transgenic mice APPswe, PS1M146V and tauP301L (3xTgAD) mice presenting the main characteristics of Alzheimer's disease (AD). COB231 labelled amyloid plaques on brain slices of AD patients, and 3xTgAD mice at 10 and 0.1 μM respectively. However, no labelling of the neurofibrillary tangle‐rich areas was observed either at high concentration or in the brain of fronto‐temporal dementia patients. The specificity of this mapping was attested in mice using Thioflavin S and IMPY as positive controls of amyloid deposits. After intravenous injection of COB231 in old 3xTgAD mice, fluorescent amyloid plaques were detected in the cortex and hippocampus, demonstrating COB231 blood–brain barrier permeability. We also controlled the cellular localization of COB231 on primary neuronal cultures and showed that COB231 accumulates into the cytoplasm and not into the nucleus. Finally, using a viability assay, we only detected a slight cytotoxic effect of COB231 (< 10%) for the highest concentration (100 μM). Previous work has shown that naturally fluorescent proflavine derivatives label Abeta plaques. Our aim was to further characterize the properties of one of them: 3‐acetylamino‐6‐[3‐(propargylamino) propanoyl]aminoacridine (COB231). We demonstrated the Abeta deposit binding properties of COB231 in vitro on Alzheimer (AD) patient brain slices (see image showing COB231 labelling of Abeta deposits), and in vivo in an AD mice model. These results are particularly attractive with regard to the flexible chemistry of COB231 that allows further radiolabelling for in vivo imaging or combination with a therapeutic agent targeting Abeta aggregates. Previous work has shown that naturally fluorescent proflavine derivatives label Abeta plaques. Our aim was to further characterize the properties of one of them: 3‐acetylamino‐6‐[3‐(propargylamino) propanoyl]aminoacridine (COB231). We demonstrated the Abeta deposit binding properties of COB231 in vitro on Alzheimer (AD) patient brain slices (see image showing COB231 labelling of Abeta deposits), and in vivo in an AD mice model. These results are particularly attractive with regard to the flexible chemistry of COB231 that allows further radiolabelling for in vivo imaging or combination with a therapeutic agent targeting Abeta aggregates.